Biology subjects

Bardet, A.

Publications and source records attributed to Bardet, A..

3 recordsLinked to original sources

bioRxiv2025

Sex-divergent brain epigenetic reprogramming by chronic opioids

Opioid use disorder (OUD) is a chronic condition that exhibits sex differences in prevalence, symptoms and treatment. Yet, the epigenetic mechanisms underlying these differences remain largely unknown. Here, we investigated the nucleus accumbens, a key brain region in OUD, to define the multiomic consequences of chronic morphine exposure in male and female mice. We profiled DNA methylation, five histone post-translational modifications, and their transcriptional effects at bulk and cell-type-specific levels. Despite comparable tissue organization and neurophysiological responses to morphine, epigenetic adaptations occurred at highly sex-specific genomic loci. These adaptations nevertheless followed common mechanistic principles, acting at similar gene features and transcription factor binding sites across sexes. Strikingly, they converged on overlapping genes, biological functions, and co-expression modules, and partially recapitulated transcriptional signatures of OUD in men and women. Therefore, our findings uncover a profound epigenetic sex divergence that mediates convergent biological dysregulation, and highlight opportunities for developing improved therapeutic strategies tailored to sex-specific mechanisms.

neuroscience↗

bioRxiv2025

Biophysical Modeling Uncovers Transcription Factor and Nucleosome Binding on Single DNA Molecules

Gene regulation in eukaryotes emerges from a dynamic interplay between transcription factors (TFs), nucleosomes, and RNA Polymerase II (Pol II), whose competitive and cooperative binding shapes DNA accessibility and transcriptional output. Single-molecule footprinting (SMF) and long-read chromatin accessibility assays such as Fiber-seq now capture these interactions at nucleotide resolution on individual DNA molecules. However, existing computational tools remain insufficient to decode complex binding events from sparse methylation data. Here, we introduce HiddenFoot, a probabilistic modeling framework based on statistical mechanics that quantitatively infers TF, nucleosome, and Pol II occupancy profiles on single DNA molecules by systematically evaluating all thermodynamically plausible binding configurations. Applying HiddenFoot to SMF and Fiber-seq data from mouse, Drosophila, and human cells, we recovered known TF footprints, precisely resolved Pol II pausing, and identified extensive heterogeneity in nucleosome positioning driven by TF binding. HiddenFoot further distinguishes direct TF-TF cooperativity from nucleosome-mediated co-dependency by estimating pairwise interaction energies and comparing to null models under equilibrium. By integrating biophysical modeling with high-resolution single-molecule data, HiddenFoot offers a general, interpretable framework for dissecting regulatory logic in native chromatin with base-pair precision. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/653852v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@46f3b5org.highwire.dtl.DTLVardef@2a2cbdorg.highwire.dtl.DTLVardef@df42f2org.highwire.dtl.DTLVardef@1a4205d_HPS_FORMAT_FIGEXP M_FIG C_FIG

genomics↗

bioRxiv2024

Conserved Cis-Acting Range Extender Element Mediates Extreme Long-Range Enhancer Activity in Mammals

While most mammalian enhancers regulate their cognate promoters over moderate distances of tens of kilobases (kb), some enhancers act over distances in the megabase range. The sequence features enabling such extreme-distance enhancer-promoter interactions remain elusive. Here, we used in vivo enhancer replacement experiments in mice to show that short- and medium-range enhancers cannot initiate gene expression at extreme-distance range. We uncover a novel conserved cis-acting element, Range EXtender (REX), that confers extreme-distance regulatory activity and is located next to a long-range enhancer of Sall1. The REX element itself has no endogenous enhancer activity. However, addition of the REX to other short- and mid-range enhancers substantially increases their genomic interaction range. In the most extreme example observed, addition of the REX increased the range of an enhancer by an order of magnitude, from its native 71kb to 840kb. The REX element contains highly conserved [C/T]AATTA homeodomain motifs. These motifs are enriched around long-range limb enhancers genome-wide, including the ZRS, a benchmark long-range limb enhancer of Shh. Mutating the [C/T]AATTA motifs within the ZRS does not affect its limb-specific enhancer activity at short range, but selectively abolishes its long-range activity, resulting in severe limb reduction in knock-in mice. In summary, we identify a sequence signature globally associated with long-range enhancer-promoter interactions and describe a prototypical REX element that is necessary and sufficient to confer extreme-distance gene activation by remote enhancers.

genomics↗